Reevaluation of ceftazidime dosing recommendations in patients on continuous ambulatory peritoneal dialysis

Abstract

While intraperitoneal (i.p.) ceftazidime is commonly used to treat continuous ambulatory peritoneal dialysis (CAPD)-related infections, the ability of i.p. regimens to achieve critical pharmacodynamic targets in both blood and dialysate has not been reported. To understand the pharmacodynamic profile of ceftazidime during CAPD, data were obtained from a single-dose pharmacokinetic (PK) i.p. ceftazidime study that included 10 CAPD patients who received i.p. ceftazidime at 15 mg/kg of body weight. The probability of target attainment (concentrations maintained above the MIC for >60% of the dosing interval [60% T > MIC]) was determined for six simulated regimens. A 3-compartment model with each dialysis dwell modeled as a separate differential equation was fit to ceftazidime concentrations using BigNPAG. Embedded with the final PK model, serum and dialysate concentration-time profiles of ceftazidime at 1, 1.5, and 2 g i.p. every 24 h (q24h) to q48h were simulated using ADAPT 5. The mean population pharmacokinetic parameters were as follows: apparent volume of the central compartment (Vc), 7.57 liter; apparent volume of the peritoneal cavity (Vpd), 2.44 liter; clearance from the central compartment (CL), 0.379 liter/h; intercompartmental transfer rate constants (first order) between the central and peripheral compartments (k12 and k21), 4.66 and 4.88 h(-1), respectively; and intercompartmental transfer rate constants (first order) between the central and peritoneal compartments (k13 and k31), 0.111 and 0.227 h(-1), respectively. In serum, the probability of target attainment for MICs of ≤8 mg/liter exceeded 90% for 1.5 to 2 g i.p. q24h to q48h. However, no tested regimen provided adequate dialysate exposure at MICs of ≥8 mg/liter on day 1 without the use of a 3-g loading dose (post hoc analysis). On day 2, 1.5 to 2 g i.p. q24h or 2 g i.p. q48h provided adequate exposure in the peritoneal cavity. These results should be validated in the presence of infection. Ceftazidime i.p. at 1.5 or 2 g q24h to q48h is recommended for nonperitoneal infections. For peritonitis, a 3-g load with maintenance dosing of 1 to 2 g i.p. q24h or 2 g i.p. q48h is recommended.

Figures

FIG 1

Observed versus predicted plots for serum concentrations (A) and peritoneal cavity concentrations during dwell 1 (B) and dwell 4 (C).

FIG 2

Serum (A) and peritoneal (B) ceftazidime concentration versus time profiles.

FIG 3

Probability of target attainment for intraperitoneal ceftazidime dosing regimens during day 1 (0 to 24 h).

FIG 4

Probability of target attainment for intraperitoneal ceftazidime q24h dosing regimens during day 2 (24 to 48 h).

FIG 5

Probability of target attainment for intraperitoneal ceftazidime q48h dosing regimens during day 2 (24 to 48 h).

FIG 6

Probability of target attainment for intraperitoneal ceftazidime q48h dosing regimens for entire dosing interval (0 to 48 h).